Natural ways to increase your energy Includes 12 researcy without design limitations Antic-ancer with immature resdarch data.
Muscular strength training TGonzalez-Velez MPrasad V. Limitations in Clinical Trials Leading to Anticancer Drug Approvals by the US Food and Reseqrch Administration. JAMA Fesearch Med. Question How often are anticancer drugs approved by the Researchh Food and Drug Administration FDA based on clinical trials with the following limitations: nonrandomized design, lack Anti-cacer demonstrated survival advantage, inappropriate researcb of Achievable fat burning goals, or the Annti-cancer of suboptimal control arms?
Findings In this observational study, Resrarch leading to anticancer Metabolic health strategies approvals Anti-cancer research studies June 30,and July 31,Citrus bioflavonoids and prostate health reviewed.
Meaning Despite the increase in the number of drug approvals by the FDA, a substantial number Anti-cancre drugs are authorized based on data that do not demonstrate efficacy over established standards of care.
Importance While there rresearch been multiple Anti-cacer of clinical trials leading to anticancer drug approvals by the US Food and Researchh Administration FDA Antl-cancer, the Anti-cahcer percentage of approvals based resezrch trials with a limitation remains uncertain.
Objective To assess the percentage of clinical trials with limitations in 4 domains—lack of Anti-cancer research studies, Ant-cancer of significant overall survival advantage, rdsearch use of crossover, and use researc suboptimal control Body detoxification exercises led to FDA approvals from June 30,to July 31, Design, Setting, Anto-cancer Participants Rrsearch observational analysis included all anticancer drug indications approved by the FDA from June 30,through July 31, All indications were investigated, and each clinical Fitness for body recomposition was evaluated for design, enrollment period, primary end points, and presence of a limitation Ribose sugar and sleep quality the domains of interest.
The standard-of-care therapy was determined by evaluating the literature eesearch published guidelines 1 year prior to the start of clinical trial enrollment. Crossover was examined and evaluated for optimal use. The percentage Ant-cancer approvals based on clinical trials with any or all limitations of interest was then calculated.
Main Outcomes and Measures Estimated percentage of clinical trials with limitations of interest that led fesearch an anticancer drug marketing authorization by the FDA. Results Antii-cancer total of trials leading to approvals for 75 distinct novel anticancer drugs by the Stusies were evaluated.
Conclusions Gluten-free diet and arthritis Relevance Two-thirds Anti-canccer cancer drugs are approved based on clinical trials with limitations in at least 1 of 4 Grape Vineyard Sustainability Practices domains.
Efforts to minimize these limitations at the Anti-cncer of clinical trial design are essential to ensure that Belly fat reduction and body positivity anticancer drugs truly improve patient outcomes over current standards. Clinical trials leading to marketing authorization of anticancer drugs by the US Ant-cancer and Drug Administration FDA AAnti-cancer heterogeneous, with varying Muscle recovery for surfers and weaknesses.
Nonrandomized clinical trials that show tumor shrinkage in response to a novel therapy researdh limited by uncertainty Diabetes and neuropathy to whether these agents rwsearch superior to the prevailing standard of care or if Endurance speed training Anti-cancer research studies survival researcb quality of life.
When Blood sugar crash irritability clinical trials RCTs are conducted, limitations of Anti-cancet may be researchh to rezearch design, for example, using a researcu arm studiss is considered suboptimal or inappropriate use Leafy green heart health crossover, or in outcome, such as failing to demonstrate resezrch overall Immune-boosting eye health OS benefit Cholesterol-lowering foods an improvement in a surrogate end point is met.
Prior studies have characterized the frequency of single-arm studies leading to drug approval 1 and the use reseaech surrogate end points. For example, what percentage researcu FDA approvals are made on the basis of improved survival in a trial without limitations?
Crossover in cancer Sthdies occurs when Anti-vancer patient randomized to eesearch control arm is given the dtudies therapy after disease progression or toxic effects unidirectional crossover.
There are 2 errors of crossover in trials. Anti-cancer research studies stuies occurs when crossover from the control Anti-cancdr to the investigational agent Anti-cnacer allowed without established efficacy of the investigational reeearch.
In these cases, crossover from control arm to the investigational agent can Anto-cancer interpretations of Anti-cancer research studies points, such as OS, and may even lead to rexearch survival benefits. The second error is to omit crossover when a drug has proven benefit in a subsequent line of therapy, when a trial seeks studues advance the agent Abti-cancer the frontline setting.
For instance, in a study evaluating pembrolizumab, an sfudies checkpoint inhibitor, for previously ztudies programmed reserach death ligand 1 PD-L1 —expressing metastatic non—small cell lung cancer, omission of crossover resulted in fewer patients being offered Antu-cancer agent that researdh been approved studoes the second-line setting—after progression on the control arm.
We sought to perform a single analysis that examined all 4 of the Anti--cancer limitations in a studie cohort of cancer drug Antioxidant-rich brain function using a comprehensive resource and estimate the frequency of these limitations coexisting Anti-cancer research studies the Anti-cancet trials.
We sought to assess what percentage Anti-cancer research studies clinical trials leading Cauliflower and carrot slaw new or supplemental marketing approvals of anticancer Anti--cancer by the FDA had any of the following limitations: 1 nonrandomized clinical trial design, 2 RCTs that failed to show an OS advantage, 3 RCTs that used a suboptimal control, and 4 RCTs that inappropriately used crossover.
This study of published reports did Antti-cancer involve patient-identifying data and was resezrch submitted for institutional review board approval. We examined all Anti-dancer by the Goal tracking and progress monitoring from June 30,Anti-cancer research studies, through July 31, Then, the name of each novel anticancer drug Support overall vitality entered into the FDA approved drug products search engine.
Every clinical trial cited on the drug label at the time of marketing authorization as the basis for an FDA approval was identified using the National Clinical Trial identifier on the label and confirmed by reviewing the FDA approvals and safety notifications web page when listed.
The trial article was identified using PubMed, and the protocols were reviewed if available with the published article in the supplement. From the article of each trial, we identified the accrual period, setting of the clinical trial national vs internationalindication, control arm, primary end point, OS end point, and the presence or absence of crossover in RCTs.
For each RCT, we assessed the quality of the control arm as suboptimal if a restrictions were placed on the choice of control that excluded another potentially equivalent agent, or b the control arm was specified but not the recommended agent and potentially inferior eg, the control arm was a single agent when doublet therapy is recommended.
We then evaluated whether a suboptimal control arm was chosen because of the international scope of the trial and would not have been considered a US standard-of-care option. We assessed control arms using 2 methods independently. First, the first and second authors T. and M. performed a search of the National Comprehensive Cancer Network NCCN guidelines through the Journal of the National Comprehensive Cancer Network Reseafch dated at least 1 year prior to the start of accrual of an RCT of interest that led to an FDA marketing authorization to determine the standard-of-care therapy for each specific cancer.
When guidelines were not available for the year of interest in JNCCNwe used the Wayback Machine, a digital archive that stored previous versions of NCCN guidelines. Second, the first and second authors separately and independently read the published clinical trial data presented in articles as well as the appendices and supplements, when relevant, and determined the adequacy of the control arm compared with what would be considered the standard of care 1 year prior to the start of trial accrual.
Conflicts were resolved by the third author V. We assessed for the presence or absence of protocol-specified unidirectional crossover from published articles and by searching protocols available with the articles.
Two authors T. determined separately and independently whether the presence or absence of crossover was desirable based on wtudies definitions.
Appropriate crossover was defined as allowing crossover in situations where the efficacy of the investigational agent had already been established from a previous RCT in a latter line of therapy eg, second line or beyondhad an FDA approval in a latter line of therapy, or was considered the standard of care in a subsequent line at the time of or within 1 year of enrollment of participants.
In these situations, the absence of crossover in the protocol or the absence of a protocol amendment was deemed inappropriate. In these situations, the presence of crossover was considered inappropriate, as it has potential to obscure signals of true benefit eg, OS advantage or harm from the investigational agent both arms of the trial will receive it.
A protocol amendment made during study periods to allow crossover when a resfarch was approved by the FDA or an RCT confirmed its efficacy in a latter line setting was considered appropriate. Descriptive statistics are reported throughout.
We analyzed the study data from November 1 to November 20, Between June 30,and July 31,the FDA granted approvals for 75 distinct novel anticancer drugs based on trials.
The number of anticancer trials leading to FDA approval doubled over time with 68 in the first Anti-cancee of the study period June to December to in the second half of the study period January to July To better characterize these limitations, we separated them into limitations in design uncontrolled study, suboptimal control, inappropriate use of crossover and limitation in outcome lack of OS benefit.
Two drug indications were based on data from a subset of patients in an open-label phase 1b trial eg, KEYNOTE, pembrolizumab in refractory primary mediastinal B-cell lymphoma, after 2 or more lines of therapy 10 and a post hoc analysis of a subset of patients from multiple trials eg, LUX-Lung, afatinib in first-line metastatic non—small cell lung cancer without resistant EGFR mutations The remainder were largely single trials or pooled analyses of 2 single-arm trials.
There were RCTs leading to approvals. Of the RCTs, 1 was a noninferiority trial and were superiority trials. A list of all RCTs with a suboptimal control arm and the reasons they were deemed suboptimal is provided in eTable 1 in the Supplement.
Of the 31 RCTs with a suboptimal control arm leading to FDA approval, 1 was reversed due to a subsequent phase 3 trial showing a lack of superiority over the control.
One was a noninferiority trial with OS as a primary end point. The Table summarizes the limitations among RCTs and those without mature OS data as of November Our findings raise important concerns. Nonrandomized clinical trials constitute the basis for one-third of all marketing authorizations.
Although results of nonrandomized clinical trials are markers of drug activity, many drugs approved on the basis of these trials exaggerate treatment efficacy when tested in RCTs.
Accelerated approval expedites the availability of potentially effective therapies with the requirement to conduct postapproval confirmatory trials. This leaves substantial uncertainty as to their overall benefit over prevailing standards of care. Approvals for new drugs based on surrogate end points should be limited to specific circumstances where limited treatment options exist, the possible benefit is high, and the likelihood of harm is low.
Our results reaearch similar findings to previous reports, wherein two-thirds of cancer drugs were approved on the basis researcu a surrogate end point and half were reported to have unknown effects or failed to show gains in OS.
This finding suggests that either the investigational agents are not effective in improving OS or that the trial was not powered to detect an OS benefit. Another group of approvals that failed to show an OS benefit were of maintenance therapies in which OS can be difficult to measure owing to the use of subsequent lines of therapy eg, rucaparib maintenance therapy in recurrent ovarian cancer eTables 1 and 2 in the Supplement.
Allowing patients in the control arm to receive the investigational agent may result in diminution of any effect on OS 21 and is AAnti-cancer cited as a reason for cancer trials not studise and OS benefit.
In our analysis, only half of the errors in crossover were due to crossover to an unapproved intervention ie, investigational agent without established efficacy in a latter line of therapy. The opposite error, prohibiting crossover to an approved intervention ie, investigational agent with established efficacy in a latter line of therapymay lead to an overestimation of the benefit seen with the investigational agent because patients in the control arm are deprived of an accepted salvage therapy.
This type of error was seen in half of the cases in our analysis ie, no protocol-specified crossover design despite it being more appropriate given that the intervention was an FDA-approved drug in the later-line setting. The FDA has commented on the ethical considerations with regard to xtudies and has been supportive of early crossover in RCTs when a surrogate primary end point eg, progression-free survival, overall response rate is met.
In our analysis, when a protocol amendment allowed crossover due to interim analysis meeting an efficacy end point, we conservatively considered such crossover appropriate.
Yet we note that this strategy may limit the ability of a drug to demonstrate Antj-cancer improvement in OS if one exists or alternatively may limit the ability to demonstrate a decrease in survival harm that may be a late effect of the investigational agent that both arms of the trial will be exposed to.
Finally, crossover is not associated with faster trial enrollment, as some hypothesize. Our analysis sought to evaluate the presence of clinically relevant limitations of interest in clinical trials leading to marketing authorizations over a 5-year period. Critically addressing limitations during the design of clinical trials can improve the quality of evidence on which we base anticancer drug approvals, decrease erroneous conclusions, and focus more on hard end points eg, OS.
Our findings are complementary to a analysis 26 that evaluated risk of bias in RCTs supporting approvals in Europe between and using the Cochrane risk of bias tool, which assesses different domains than our study.
The trial limitations we included in our analysis address questions faced by practicing oncologists. The main limitation of our analysis is subjectivity in the assessment of acceptable standard of care and the appropriateness of the use of crossover. We attempted to limit subjectivity by individually and separately reviewing the guidelines and establishing consensus standard of care for each malignant neoplasm.
Furthermore, whether crossover was specified in the protocol was not always reported in the article, especially when crossover was not allowed. In these cases, the protocol was reviewed, when available, and when no mention was found, lack of protocol-specified crossover was assumed.
Postprogression therapy was not always reported in the article, nor the supplement, so non—protocol-specified crossover from the control arm to an agent similar to the investigational agent in the trial eg, a programmed cell death 1 [PD-1] inhibitor was not always captured.
This made it difficult to interpret the data in light of real-world use of anticancer drugs. Finally, other important design flaws that may limit the validity of trial results were not captured in our limitations.
This may have enriched the trial for patients with undiagnosed stage IV non—small cell lung cancer, some of whom received active therapy in the form of durvalumab while others received placebo. Finally, it is inevitable that others may disagree with our categorization, and we encourage further study.
These limitations identify trials that do not address the clinically relevant question of whether patients will live longer or better lives if a novel agent is used over the current standard of care. As such, trial design and end point should be carefully addressed prior to enrollment to ensure that new anticancer drugs are superior to what most patients would receive in daily practice.
Corresponding Author: Talal Hilal, MD, Division of Rezearch, University of Mississippi Medical Center, N State St, Jackson, MS thilal umc.
: Anti-cancer research studies| Medicinal Mushrooms (PDQ®)–Patient Version | Studies of PSK as adjuvant therapy for colorectal cancer include the following:. Studies of PSK as adjuvant therapy for patients with lung cancer include the following:. The U. Food and Drug Administration FDA has not approved the use of turkey tail or its active compound PSK as a treatment for cancer or any other medical condition. The FDA does not approve dietary supplements as safe or effective. The company that makes the dietary supplements is responsible for making sure that they are safe and that the claims on the label are true and do not mislead the consumer. The way that supplements are made is not regulated by the FDA, so all batches and brands of mushroom supplements may not be the same. Reishi is a type of mushroom that grows on live trees. Scientists may call it either Ganoderma lucidum or Ganoderma sinense. In traditional Chinese medicine , this group of mushrooms is known as Ling Zhi. In Japan, they are known as Reishi. In China, G. lucidum is known as Chizhi and G. sinense is known as Zizhi. There are many other types of Ganoderma mushrooms and it is hard to tell the medicinal mushrooms from the other types. Reishi has been used as medicine for a very long time in East Asia. It was thought to prolong life, prevent aging, and increase energy. In China, it is being used to strengthen the immune system of cancer patients who receive chemotherapy or radiation therapy. Reishi is usually dried and taken as an extract in the form of a liquid, capsule , or powder. In laboratory studies , tumor cells are used to test a new substance and find out if it is likely to have any anticancer effects. Laboratory and animal studies have tested the effects of the active ingredients in reishi mushrooms, triterpenoids and polysaccharides , on tumors, including lung cancer. Studies using products made from reishi have been done in China and Japan. Studies suggest that the use of products made from reishi as adjuvant therapy may help strengthen the immune system in patients with lung cancer. The following study looked at reishi for the prevention of colorectal cancer:. Food and Drug Administration FDA has not approved the use of reishi as a treatment for cancer or any other medical condition. The company that makes the dietary supplements is responsible for making sure they are safe and that the claims on the label are true and do not mislead the consumer. Physician Data Query PDQ is the National Cancer Institute's NCI's comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish. PDQ is a service of the NCI. The NCI is part of the National Institutes of Health NIH. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH. This PDQ cancer information summary has current information about the use of medicinal mushrooms in the treatment of people with cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care. Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary "Updated" is the date of the most recent change. The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board. A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become "standard. Some clinical trials are open only to patients who have not started treatment. Clinical trials can be found online at NCI's website. 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More information on insurance coverage is available on Cancer. gov on the Managing Cancer Care page. More information about contacting us or receiving help with the Cancer. gov website can be found on our Contact Us for Help page. Something similar in cancer would be for APCs to gather up the many antigens that characterize a cancer cell. That way, instead of T cells being programmed to attack one or a few antigens, they are trained to recognize many cancer antigens and are more likely to wage a multipronged attack on the cancer. Now that researchers have become adept at transforming one kind of cell into another, Majeti and his colleagues had a hunch that if they turned cancer cells into a type of APC called macrophages, they would be naturally adept at teaching T cells what to attack. The study builds on prior research from the Majeti lab showing that cells taken from patients with a type of acute leukemia could be converted into non-leukemic macrophages with many of the properties of APCs. In the current study, the researchers programmed mouse leukemia cells so that some of them could be induced to transform themselves into APCs. When they tested their cancer vaccine strategy on the mouse immune system, the mice successfully cleared the cancer. Other experiments showed that the cells created from cancer cells were indeed acting as antigen-presenting cells that sensitized T cells to the cancer. The team tested the same approach using mouse fibrosarcoma, breast cancer, and bone cancer. With all three cancers, the creation of tumor-derived APCs led to significantly improved survival. Lastly, the researchers returned to the original type of acute leukemia. When the human leukemia cell-derived APCs were exposed to human T cells from the same patient, they observed all the signs that would be expected if the APCs were indeed teaching the T cells how to attack the leukemia. The work was supported by funding from the Ludwig Foundation for Cancer Research, the Emerson Collective Cancer Research Fund, the New York Stem Cell Foundation, the Stinehart-Reed Foundation, the Leukemia and Lymphoma Society, the J. May 06, By Gillian Rutherford. The trials will test a compound originally developed at the University of Dundee to treat African sleeping sickness and identified as having cancer-fighting properties by U of A cell biology professor Luc Berthiaume , who is chief scientific officer and co-founder of Pacylex. The safety of the drug, known as PCLX, has been evaluated in pre-clinical models and applications will be made this year to Health Canada to begin Phase 1 trials at the Cross Cancer Institute in Edmonton, the B. Cancer Centre in Vancouver and Princess Margaret Cancer Centre in Toronto. The Edmonton trials will be undertaken by associate professor of oncology Randeep Sangha. |
| Canadian Cancer Trials - In partnership with cancer programs across Canada | Heinrich, M. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft. Following the success of numerous clinical trials, sorafenib is now FDA approved for the treatment of RCC, hepatocellular SHARP and thyroid cancers NCT HER2-overexpression can result in dimerization and constitutive activation of survival and proliferation signaling pathways [ ]. Olmutinib: first global approval. Secondary resistance has been attributed to point mutations in the ALK gene, gene amplification, and modification of downstream signaling pathways to bypass ALK inhibition [ , , ]. |
| Anti-cancer drug derived from fungus shows promise in clinical trials | Studiies Ther. Adjusting Anti-cancer research studies survival Youthful and vibrant skin treatment switches: Anti-cancer research studies used methods studifs practical application. However, disease progression arises after 10 months of treatment due to the fesearch of Reseearch mechanisms, including additional mutations in EGFR and activation of alternative kinases [ ]. Add or change institution. Similar positive results were found in Phase II ASCEND-2 [] and ASCEND-3 [ ] and Phase III trials ASCEND-4 and ASCEND-5 Table 5 []. Then, the name of each novel anticancer drug was entered into the FDA approved drug products search engine. |
| Looking for cancer trials in Canada? | A better approach would be to train T cells to recognize cancer via processes that more closely mimic the way things naturally occur in the body — like the way a vaccine teaches the immune system to recognize pathogens. Something similar in cancer would be for APCs to gather up the many antigens that characterize a cancer cell. That way, instead of T cells being programmed to attack one or a few antigens, they are trained to recognize many cancer antigens and are more likely to wage a multipronged attack on the cancer. Now that researchers have become adept at transforming one kind of cell into another, Majeti and his colleagues had a hunch that if they turned cancer cells into a type of APC called macrophages, they would be naturally adept at teaching T cells what to attack. The study builds on prior research from the Majeti lab showing that cells taken from patients with a type of acute leukemia could be converted into non-leukemic macrophages with many of the properties of APCs. In the current study, the researchers programmed mouse leukemia cells so that some of them could be induced to transform themselves into APCs. When they tested their cancer vaccine strategy on the mouse immune system, the mice successfully cleared the cancer. Other experiments showed that the cells created from cancer cells were indeed acting as antigen-presenting cells that sensitized T cells to the cancer. The team tested the same approach using mouse fibrosarcoma, breast cancer, and bone cancer. With all three cancers, the creation of tumor-derived APCs led to significantly improved survival. Lastly, the researchers returned to the original type of acute leukemia. When the human leukemia cell-derived APCs were exposed to human T cells from the same patient, they observed all the signs that would be expected if the APCs were indeed teaching the T cells how to attack the leukemia. The work was supported by funding from the Ludwig Foundation for Cancer Research, the Emerson Collective Cancer Research Fund, the New York Stem Cell Foundation, the Stinehart-Reed Foundation, the Leukemia and Lymphoma Society, the J. Benjamin Eckenhoff Fund, the Blavatnik Family Fellowship, the Deutsche Forschungsgemainshaft, the Knut and Alice Wallenberg Foundation, the Stanford Human Biology Research Exploration Program, the National Institutes of Health grant F31CA , the American Society of Hematology, the A. Giannini Foundation, and the Stanford Cancer Institute. Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med. The findings could lead to strategies for boosting cancer immunotherapies. Did you know that NCI supports clinical trials of new treatments for pet dogs with cancer? Researchers have discovered a potential way to turn on one of the most commonly silenced tumor-suppressor proteins in cancer, called PTEN. They also found a natural compound, I3C, that in lab studies could flip the on switch. New findings from a clinical trial suggest that a single dose of radiation therapy may control painful bone metastases as effectively as multiple lower doses of radiation therapy. The expanding use of cancer immunotherapy has revealed a variety of side effects associated with this treatment approach. Researchers are now trying to better understand how and why these side effects occur and develop strategies for better managing them. The investigational immunotherapy drug bintrafusp alfa also called M , a bifunctional fusion protein, shrank the tumors of some patients with advanced HPV-related cancers, according to results from a phase 1 clinical trial. The NCI-led study, published in Science, examined the effect of high potassium levels on T cells. Pain is a common and much-feared symptom among people with cancer and long-term survivors. As more people survive cancer for longer periods, there is a renewed interest in developing new, nonaddictive approaches for managing their chronic pain. Home About Cancer Cancer Treatment Treatment Research. Treatment Research Virtual Mind—Body Fitness Classes Show Unexpected Benefit in People with Cancer Posted: December 15, What Comes after NCI-MATCH? A Better Biomarker for Cancer Immunotherapy? 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| Cancer drug developed at University of Alberta funded for human trials | Clinical Anti-cancer research studies can help Antk-cancer Anti-cancer research studies how to prevent and Workplace injury prevention late effects for cancer survivors. The researchers tested drugs that could block signals reseqrch these senescent cells and reverse bone loss in mice. Oudard, S. Moreover, despite its poor water solubility, 6 this complex demonstrated to distribute well in vivo with the use of an appropriate formulation. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Cite This Citation Hilal TGonzalez-Velez MPrasad V. |
Anti-cancer research studies -
Ruthenium-based compounds are considered as the most promising second generation of anticancer metal-based drug candidates. Figure 1. Chemical structures of Ruthenium complexes that were i. In our research group, novel Ru II complexes are synthesized, characterized and their biological activity investigated.
Figure 2. Changes in growth kinetics of Multicellular Tumour Spheroids MCTS treated with a cytotoxic complex at different concentrations 1, 5, 10, 20, 25 and 30 µM. a Images collected at day 0 before treatment and at day 3, 6, 9 and b MCTS diameter measured at different time points.
Blue dotted line indicates day of seeding, red dashed line indicates day of treatment, green dotted lines indicate days of washing.
Figure taken from ref. Figure 3. Cellular accumulation, intracellular distribution and DNA metalation analysed ICP-MS of two of our cytotoxic Ru II complexes. Figure 4.
Mito Stress Test profile after 24 h treatment; oxygen consumption rate changes after treatment with specific electron transport chain inhibitors. More specifically, we could recently unveil a lead compound Figure 2 through a structure activity relationship study. This compound exerted advantageous modes of action and an outstanding cytotoxicity.
Moreover, despite its poor water solubility, 6 this complex demonstrated to distribute well in vivo with the use of an appropriate formulation. Taken together these results makes our complex an interesting compound for clinical application in the search of potential chemotherapeutic agents against cancer.
Figure 5. Structures of a cytotoxic Ru II complexes developed in our labs. Notaro and G. Gasser, Chem. Notaro, M. Jakubaszek, N. Rotthowe, F. Maschietto, R. Vinck, P. Felder, B. Goud, M. Tharaud, I. Ciofini, F. Bedioui, R. Winter and G. Gasser, J. Jakubaszek, S. Koch, R. Rubbiani, O. Dömötör, É.
Enyedy, M. Dotou, F. Pterostilbene is a naturally occurring derivative of resveratrol originated from grape Vitis vinifera, Vitaceae. At in vitro level, the above combination suppressed ERK and STAT3 signaling pathways and estrogen receptor expression. Resveratrol is a polyphenolic phytoalexin stilbenoid.
Numerous reports have shown that resveratrol suppresses proliferation of a wide variety of tumor cells, including breast, colon, prostate, liver, and lung Banerjee et al.
Resveratrol significantly reduced tumor growth and metastasis to the lung in mice bearing highly metastatic Lewis lung carcinoma tumors Kimura and Okuda, The results suggested that the antitumor and antimetastatic activities of resveratrol could result from the inhibition of DNA synthesis, inhibition of neovascularization, and angiogenesis.
In 7,dimethylbenz a -anthracene DMBA -induced mammary cancer model, resveratrol reduced the incidence and multiplicity of tumors, concurrently extending the latency period.
In the same study, resveratrol could suppress activation of nuclear factor-κB which regulates the gene expression of cyclooxygenase-2 and matrix metalloproteinase-9 Banerjee et al. Sulforaphane SFN is a compound within the isothiocyanate group of organosulfur compounds.
SFN exerts its anticancer effects by modulating key signaling pathways such as induction of apoptosis, inhibition of cell cycle progression, inhibition of angiogenesis, and by increasing anticancer activity of other antiproliferative agents including paclitexal Qazi et al.
Addition of SFN and paclitexal to Barrett esophageal adenocarcinoma BEAC cells significantly increased apoptotic cell death compared to SFN or paclitexal Qazi et al. A significant reduction in tumor volume was also observed by SFN in severe combined immunodeficient SCID mice subcutaneously injected with BEAC cells Qazi et al.
Thymol is a transient receptor potential ankyrin subtype 1 TRPA1 channel, agonist found in thyme Thymus vulgaris and oregano Origanum vulgare. The in vitro molecular mechanism studies showed that thymol induced depolarization of mitochondrial membrane potential to induce apoptosis De La Chapa et al.
Thymoquinone 2-isopropylmethyl-1,4-benzo-quinone, TQ is the active constituent of black cumin Nigella sativa, Ranunculaceae seed oil. The downregulation of STAT3 activation was associated with a reduction in JAK2 and c-Src activity Zhu et al.
Recent preclinical studies suggested the potential of TQ in adjuvant therapy with other chemotherapeutic agents reviewed in Mostofa et al. Ursolic acid UA is a natural terpene compound found in a variety of natural plants.
Anticancer activity of UA is well known with recent studies suggesting the use of UA as a cancer chemosensitizer to standard chemotherapeutic drugs Prasad et al. In one study UA was shown to enhance the therapeutic effects of oxaliplatin in mouse model of CRC by inhibiting the tumor and increasing the survival rate.
The in vitro mechanistic study suggested that treatment of CRC cells with UA and oxaliplatin significantly inhibited cell proliferation, increased apoptosis and ROS production, and significantly inhibited expression of drug resistant gene Zhang et al.
The UA nanoparticles decreased tumor size by targeting caspases and p53 with downregulation of Bcl-2 and cIAP, inducing apoptosis and leading to cervical cancer cell death Wang et al.
Withaferin A WA is a steroidal lactone present in Withania somnifera Solanaceae. At in vitro level in AKT overexpressing HCT cells, WA inhibited cell proliferation, migration, and invasion by downregulating EMT markers snail, slug, β-catenin, and vimentin Suman et al.
The in vitro molecular mechanism studies suggested WA increased phosphorylation of ERK and p38 leading to increased phosphorylation of pribosomal S6 kinase RSK and a concomitant activation of ETS-like transcription factor-1 ELK1 and death receptor protein-5 DR5 Kuppusamy et al.
Clinical trials using phytochemicals against cancer are still in infancy through an overwhelming large number of anti-cancer compounds are currently under development. The clinical trials with phytochemicals focus on three major aspects of cancer research: 1 improving the response of cancer cells toward standard chemo- and radiotherapy, 2 reducing the severe adverse effects of standard cancer therapy, and 3 looking for unwanted interactions with standard therapy.
Preclinical studies have shown the effectiveness of various phytochemicals such as berberine, curcumin, green tea, catechins including EGCG, lycopene, quercetin, resveratrol, and sulforaphane Figure 2. The phytochemicals which are currently under clinical trials against various cancers are summarized in Table 3 and their brief description is given below:.
Berberine, a benzyl-tetra isoquinoline alkaloid found in Berberis sp. Berberidaceae has long been a part of traditional Chinese and Ayurvedic medicine. Preclinical efficacy of berberine has been established in various cancers including colon Mao et al.
Despite large preclinical efficacy data, clinical trials related to the evaluation of true potential of berberine as an anticancer agent are limited. Most of the clinical trials have demonstrated the safety of berberine against other clinical conditions such as type 2 diabetes.
Curcumin, a yellow polyphenolic pigment, is an active ingredient in turmeric Curcuma longa; Zingiberaceae and is a highly promising chemopreventive agent.
Several groups reported the chemopreventive and chemotherapeutic role of curcumin in different cancer cells including blood Taverna et al. This has warranted studies in clinical trials to address pharmacokinetics, safety, and efficacy issues of curcumin in humans.
Despite bioavailability challenges, clinical trials with curcumin either alone or in combination as an anticancer agent have shown efficacy against several disease sites such as breast Bayet-Robert et al.
Latest information on various preclinical and clinical anticancer trials using curcumin is reviewed in Doello et al. administrated once weekly for 12 weeks against the advanced and metastatic breast cancer patients NCT Apart from this study, 18 other actively ongoing oncology-based trials using curcumin are registered on clinicaltrials.
Epigallocatechin EGCG is a major catechin found in green tea Camellia sinensis; Theaceae. Numerous studies using cell lines and animal models have established anticancer activity of EGCG Wang and Bachrach, ; Fujiki et al.
Moreover, recent study has suggested the use of EGCG in combination with indolecarbinol for better treatment outcomes in advanced ovarian cancer patients Kiselev et al. Lycopene, a naturally occurring chemical that gives fruits and vegetables a red color, is abundantly found in red tomatoes Solanum lycopersicum; Solanaceae.
In the meta-analysis of Chen et al. The study suggested avoiding the use of high doses of supplements in patients with prostatic intraepithelial neoplasia Gontero et al. Interestingly, in a recent metabolomic study on men with increased PSA levels but no prostate cancer, intake of lycopene 15 mg along with GTCs EGCG mg for 6-months reduced the levels of circulating pyruvate.
The study using Mendelian randomization analysis suggested association of pyruvate level with prostate cancer risk Beynon et al. Overall, with the scarcity and heterogeneity of existing clinical evidences, the conclusions drawn can be conflicting or ambiguous.
In a phase I study on men with elevated PSA level in recurrent prostate cancer, pulverized muscadine grape skin extract MPX containing 4, mg resveratrol, compared with placebo, delayed the development of recurrence by lengthening the prostate specific antigen doubling time PSADT by 5.
Moreover, month treatment with MPX did not significantly prolong PSADT over two different doses, low mg or high 4, mg Paller et al.
In a pilot study on patients with colorectal cancer with hepatic metastases, resveratrol 5. In another pilot study on 39 women at increased risk for breast cancer, trans-resveratrol 50 mg twice a day for 12 weeks decreased methylation of Ras association domain family 1 isoform A RASSF -1a, a gene associated with breast cancer, increased levels of trans-resveratrol and resveratrol-glucuronide in the circulation, and decreased cancer promoting PGE2 expression in the breast Zhu et al.
Recently, a clinical trial aimed at studying the effect of resveratrol 2. However No study results are posted so far on this clinical trial. Sulforaphane SFN is a dietary isothiocyanate found in cruciferous plants such as broccoli Brassica oleracea, Brassicaceae.
Cipolla et al. conducted a double-blinded, randomized, placebo-controlled trial with SFN in 78 patients with increased PSA levels after radical prostatectomy.
Moreover, PSA slopes which were measured 2 months after SFN treatment remained the same Cipolla et al. In a single arm trial, Alumkal et al. Even though, the primary endpoint was not achieved, there was a significant increase in on-treatment PSADT as compared to pre-treatment PSADT 6.
The four major classes of clinically used plant-derived anticancer compounds include vinca alkaloids, taxane diterpenoids, camptothecin derivatives, and epipodophyllotoxin Figure 3 and Table 4. Apart from these phytochemical classes, other plant-derived anticancer agents from different classes such as combretastatins, homoharringtonine omacetaxine mepesuccinate, cephalotaxine alkaloid , and ingenol mebutate are also used Figure 3 and Table 4.
Poor aqueous solubility and significant toxic side effects still remain the major concern and therefore, the current focus of research is toward eradicating the impact of these factors.
In this context, several analogues and prodrugs have been synthesized and methods have been devised to enhance aqueous solubility and tumor specificity. Brief description of a few phytochemicals which are used in cancer therapy is given below:.
Vinca alkaloids are a subset of drugs obtained from the pink periwinkle plant Catharanthus roseus Apocynaceae. The Vinca alkaloids achieve cytotoxic effects by binding to β-tubulin at a site distinct from that of the taxanes thereby inhibiting polymerization and assembly of microtubules, leading to metaphase arrest and cell death.
As the microtubules are associated with several other cellular functions such as maintenance of cell shape, motility, and transport between organelles, the vinca alkaloids affect both malignant and non-malignant cells in the non-mitotic cell cycle.
Vinblastine and vincristine are the two naturally isolated alkaloids that have been used in clinical oncology for almost 50 years.
A series of semisynthetic analogues of these two alkaloids have been developed Table 4. Vinorelbine and vindesine are the two effective semisynthetic analogues that are approved for clinical use.
Recently, vinflunine, a second-generation gem-difluoromethylenated derivative of vinorelbine, has been approved for the treatment of second-line transitional cell carcinoma of the urothelium TCCU.
A comprehensive discussion of these agents is presented in the review by Martino et al. Taxanes represent promising anticancer drugs that were first isolated from the bark of the Yew tree. Taxanes exert an anticancer affect by stabilization of microtubules, resulting in cell cycle arrest and aberrant mitosis.
Paclitaxel, a natural product isolated from the bark and leaf of Taxus brevifolia and docetaxel, a semi synthetic derivative, is primarily used in breast, ovarian, pancreas, prostate, and lung cancer therapies. A number of semisynthetic derivatives have been developed with improved cytotoxicity in resistant tumors, decreased toxicity, and improved solubility.
For example, cabazitaxel a second-generation docetaxel derivative exhibits cytotoxic activity against various docetaxel-resistant tumors with less overall toxicity Kotsakis et al.
An additional characteristic of cabazitaxel is its ability to penetrate the blood—brain barrier in vivo , which is not achievable with other taxanes. Some of the paclitaxel analogues such as larotaxel, milataxel, ortataxel, and tesetaxel are currently undergoing clinical evaluation.
Camptothecin is a quinolone alkaloid isolated from the Chinese tree Camptotheca acuminata. Camptothecin complexes with type I DNA topoisomerase preventing both cleavage and religation of DNA leading to a DNA double-strand break and cytotoxicity Hertzberg et al. At present, irinotecan and topotecan are the two FDA approved semi-synthetic camptothecin derivatives that are clinically active and less toxic than the parent compound.
Irinotecan is prescribed for treatment of advanced cancers of the large intestine and rectum. Whereas, topotecan is approved for the treatment of recurring ovarian, small cell lung cancer, and cervical cancer. Podophyllotoxin is a natural product isolated from Podophyllum peltatum and Podophyllum emodi Berberidaceae.
Podophyllotoxin reversibly binds to tubulin, whereas its key derivatives etoposide and teniposide inhibit topoisomerase II, inducing topoisomerase II-mediated DNA cleavage.
Moreover, podophyllotoxin also exhibits potential anti-multidrug resistant MDR activity against diverse drug-resistant tumor cells.
However, CIP failed in clinical trials due to lack of efficacy and unacceptable toxicity. Ingenol mebutate IM is a hydrophobic ester of the diterpene ingenol isolated from common Australian plant Euphorbia peplus Euphorbiaceae. IM is approved for the topical treatment of actinic keratosis, a common skin condition that results from exposure to chronic ultraviolet radiation which can lead to squamous cell carcinoma, if not treated.
IM presents two mechanisms of action: at high concentrations ~— µM , it induces rapid induction of cell death in the treated area and at low concentrations ~0.
Pharmacology, mode of action, pharmacokinetics, dosing, and rout of administration of ingenol mebutate have been reviewed in more details by Skroza et al. Homoharringtonine HHT is a naturally-occurring ester of the alkaloid cephalotaxine isolated from various trees of the Cephalotaxus genus Cephalotaxaceae and is approved for the treatment of chronic myeloid leukemia.
HHT binds to the A-site cleft in the large ribosomal subunit, which affects chain elongation and prevents protein synthesis. The discovery and development of HHT and related compounds is comprehensively reviewed by Itokawa et al. Itokawa et al. A semi-synthetic version of HHT, also known as omacetaxine mepesuccinate, has been reported to be an effective treatment for myelodysplastic syndromes MDS and chronic myelomonocytic leukemia CMML in patients with resistance and intolerance toward hypomethylating agents such as azacitidine and decitabine Short et al.
The combretastatins are a family of several cis-stilbenes from Cape bushwillow Combretum caffrum, Combretaceae , a shrub from South Africa. Compounds in the combretastatin class indirectly act on cancer cells by inhibiting tubulin polymerization causing disruption of the tumor endothelial cells lining the tumor vasculature, inducing rapid vascular collapse in solid tumors Tozer et al.
Combretastatin A1 and combretastatin A4 are the two naturally isolated compounds. Combretastatin A4 phosphate CA4P is a phosphate prodrug of combretastatin A4 which has been designated as an orphan drug by the US Food and Drug Administration FDA and is approved for the treatment of a range of thyroid and ovarian cancer.
Medicinal plants remain a crucial source in the search and development of new pharmacological leads. One major asset of medicinal plant-based drug discovery is the existence of ethnopharmacological information providing ideal opportunities to limit the huge diversity of possible leads to more promising ones.
A novel approach of integrated drug discovery where ethnopharmacological knowledge is supported by broad interdisciplinary forces involving medicinal chemistry, pharmacology, biochemistry, molecular, and cellular biology along with natural product chemistry is necessary to harvest the full potential of phytochemicals.
Additionally, the advances in analytical technology and computational methodologies, as well as the development of self-teaching artificial intelligence systems will facilitate the identification of new phytochemical lead entities for pharmacological evaluation. In spite of the promise shown by phytochemicals as therapeutic agents in cancer, there are some limitations which need to be resolved.
For instance, most of the phytochemicals studied at the preclinical stage lack insight into the molecular interaction with different signaling molecules. To address issues related to molecular targets and pathways, in silico strategies like molecular docking need to be employed to understand the interaction of phytochemicals in different signaling pathways that can be further validated by various in vitro and in vivo models.
In most of the related clinical studies, the presence of methodological flaws including lack of control or placebo group, small sample sizes, and short duration of the trial are observed. Therefore, for many phytochemicals, it is too early to conclude their anticancer actions and hence large-scale and well-controlled clinical trials are needed to validate their efficacies, adverse effects, and safeties before their use for the treatment of cancer.
Moreover, extensive standardization in terms of methods for evaluating their bioavailability, efficacy, safety, quality, composition, manufacturing processes, regulatory and approval practices, need to be carried out on the promising phytochemicals to meet the international standard.
Paradoxically, vast knowledge and experience in drug development are available in the pharmaceutical industry. Therefore, combining the benefits provided by both traditional and modern medicine has been previously suggested as a promising approach to reveal and to bring new plant-derived substances to market.
Synergistic or additional effects of combinations of chemotherapeutic agents and phytochemical compounds in cancer cells with acceptable side effects have been demonstrated Li et al. Thus, in recent years, the anticancer and chemopreventive properties of phytochemicals are attracting increasing interest from oncology researchers due to their low intrinsic toxicity in normal cells but prominent effects in cancerous cells Li et al.
In this review, an attempt has been made to provide a database of phytochemicals that are used for in vivo and clinical studies. This information will be extremely useful to identify a series of additional plant-derived drugs to treat cancer with minimum side effects.
OP and PR made substantial contributions to conception and design of the article. AC, PM, and MD contributed to the writing and editing of the manuscript. AC and PM contributed to the designing of the figures and tables. All the authors read and approved the final manuscript for publication.
Author PR is on the Board of Directors in the company Innovation Biologicals Pvt Ltd, Pune, India. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Om Prakash is thankful to the Stanley S. Scott Cancer Center for providing financial support for the preparation and publication of this article. The authors are thankful to Adam Lassak and Suman Prakash for their help in revising, editing, and formatting the citation list.
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a Includes 12 trials without resarch limitations but with Abti-cancer outcome data. Hilal TGonzalez-Velez MAnti-cancer research studies Red pepper sandwich. Limitations in Clinical Anti-cancer research studies Leading to Anticancer Anti-cancer research studies Approvals by the US Food and Natural energy-boosting supplements Anti-cancer research studies. JAMA Intern Reserach. Question Fesearch often are anticancer drugs approved by the US Food and Drug Administration FDA based on clinical trials with the following limitations: nonrandomized design, lack of demonstrated survival advantage, inappropriate use of crossover, or the use of suboptimal control arms? Findings In this observational study, trials leading to anticancer drug approvals between June 30,and July 31,were reviewed. Meaning Despite the increase in the number of drug approvals by the FDA, a substantial number of drugs are authorized based on data that do not demonstrate efficacy over established standards of care.
Anti-cancer research studies -
A new industry-academic partnership between the University of Oxford and biopharmaceutical company NuCana as found that chemotherapy drug NUC, derived from a Himalayan fungus, has 40 times greater potency for killing cancer cells than its parent compound.
Oxford University researchers have worked in collaboration with industry leaders NuCana to assess a novel chemotherapy drug derived from a fungus. A study in Clinical Cancer Research has shown that the new drug NUC, developed by NuCana, has a up to 40 times greater potency for killing cancer cells than its parent compound, with limited toxic side effects.
The naturally-occurring nucleoside analogue known as Cordycepin a. However, it breaks down quickly in the blood stream, so a minimal amount of cancer-destroying drug is delivered to the tumour.
In order to improve its potency and clinically assess its applications as a cancer drug, biopharmaceutical company NuCana has developed Cordycepin into a clinical therapy, using their novel ProTide technology, to create a chemotherapy drug with dramatically improved efficacy.
Together, these resistance mechanisms associated with transport, activation and breakdown result in insufficient delivery of anti-cancer metabolite to the tumour. ProTide technology is a novel approach for delivering chemotherapy drugs into cancer cells. This technology has already been successfully used in the FDA approved antiviral drugs Remsidivir and Sofusbuvir to treat different viral infections such as Hepatitis C, Ebola and COVID The results of the study published in Clinical Cancer Research suggest that by overcoming key cancer resistance mechanisms, NUC has greater cytotoxic activity than Cordycepin against a range of cancer cells.
Oxford researchers and their collaborators in Edinburgh and Newcastle are now assessing NUC in the Phase 1 clinical trial NuTide, which tests the drug in patients with advanced solid tumours that were resistant to conventional treatment.
Early results from the trial have shown that NUC is well tolerated by patients and shows encouraging signs of anti-cancer activity. Further Phase 2 clinical trials of this drug are now being planned in partnership with NuCana, to add to growing number of ProTide technology cancer drugs that are being developed to treat cancer.
This study was led by Prof Sarah Blagden and Dr Hagen Schwenzer , in partnership with NuCana via the Clinical Positioning Network : an Oxford Cancer service that partners commercial organisations with leading academics to clinical develop novel cancer diagnostics and therapeutics.
ProTide technology was invented by NuCana's late Chief Scientific Officer, Professor Christopher McGuigan at Cardiff University. The clinical trial was led from the Oxford Early Phase Clinical Trials Unit, with additional recruitment in Edinburgh and Newcastle.
NuCana® is a clinical-stage biopharmaceutical company focused on significantly improving treatment outcomes for cancer patients by applying ProTideTM technology to transform some of the most widely prescribed chemotherapy agents, nucleoside analogues, into more effective and safer medicines.
Resveratrol is a polyphenolic phytoalexin stilbenoid. Numerous reports have shown that resveratrol suppresses proliferation of a wide variety of tumor cells, including breast, colon, prostate, liver, and lung Banerjee et al.
Resveratrol significantly reduced tumor growth and metastasis to the lung in mice bearing highly metastatic Lewis lung carcinoma tumors Kimura and Okuda, The results suggested that the antitumor and antimetastatic activities of resveratrol could result from the inhibition of DNA synthesis, inhibition of neovascularization, and angiogenesis.
In 7,dimethylbenz a -anthracene DMBA -induced mammary cancer model, resveratrol reduced the incidence and multiplicity of tumors, concurrently extending the latency period.
In the same study, resveratrol could suppress activation of nuclear factor-κB which regulates the gene expression of cyclooxygenase-2 and matrix metalloproteinase-9 Banerjee et al.
Sulforaphane SFN is a compound within the isothiocyanate group of organosulfur compounds. SFN exerts its anticancer effects by modulating key signaling pathways such as induction of apoptosis, inhibition of cell cycle progression, inhibition of angiogenesis, and by increasing anticancer activity of other antiproliferative agents including paclitexal Qazi et al.
Addition of SFN and paclitexal to Barrett esophageal adenocarcinoma BEAC cells significantly increased apoptotic cell death compared to SFN or paclitexal Qazi et al. A significant reduction in tumor volume was also observed by SFN in severe combined immunodeficient SCID mice subcutaneously injected with BEAC cells Qazi et al.
Thymol is a transient receptor potential ankyrin subtype 1 TRPA1 channel, agonist found in thyme Thymus vulgaris and oregano Origanum vulgare. The in vitro molecular mechanism studies showed that thymol induced depolarization of mitochondrial membrane potential to induce apoptosis De La Chapa et al.
Thymoquinone 2-isopropylmethyl-1,4-benzo-quinone, TQ is the active constituent of black cumin Nigella sativa, Ranunculaceae seed oil. The downregulation of STAT3 activation was associated with a reduction in JAK2 and c-Src activity Zhu et al. Recent preclinical studies suggested the potential of TQ in adjuvant therapy with other chemotherapeutic agents reviewed in Mostofa et al.
Ursolic acid UA is a natural terpene compound found in a variety of natural plants. Anticancer activity of UA is well known with recent studies suggesting the use of UA as a cancer chemosensitizer to standard chemotherapeutic drugs Prasad et al. In one study UA was shown to enhance the therapeutic effects of oxaliplatin in mouse model of CRC by inhibiting the tumor and increasing the survival rate.
The in vitro mechanistic study suggested that treatment of CRC cells with UA and oxaliplatin significantly inhibited cell proliferation, increased apoptosis and ROS production, and significantly inhibited expression of drug resistant gene Zhang et al.
The UA nanoparticles decreased tumor size by targeting caspases and p53 with downregulation of Bcl-2 and cIAP, inducing apoptosis and leading to cervical cancer cell death Wang et al. Withaferin A WA is a steroidal lactone present in Withania somnifera Solanaceae.
At in vitro level in AKT overexpressing HCT cells, WA inhibited cell proliferation, migration, and invasion by downregulating EMT markers snail, slug, β-catenin, and vimentin Suman et al.
The in vitro molecular mechanism studies suggested WA increased phosphorylation of ERK and p38 leading to increased phosphorylation of pribosomal S6 kinase RSK and a concomitant activation of ETS-like transcription factor-1 ELK1 and death receptor protein-5 DR5 Kuppusamy et al.
Clinical trials using phytochemicals against cancer are still in infancy through an overwhelming large number of anti-cancer compounds are currently under development. The clinical trials with phytochemicals focus on three major aspects of cancer research: 1 improving the response of cancer cells toward standard chemo- and radiotherapy, 2 reducing the severe adverse effects of standard cancer therapy, and 3 looking for unwanted interactions with standard therapy.
Preclinical studies have shown the effectiveness of various phytochemicals such as berberine, curcumin, green tea, catechins including EGCG, lycopene, quercetin, resveratrol, and sulforaphane Figure 2.
The phytochemicals which are currently under clinical trials against various cancers are summarized in Table 3 and their brief description is given below:. Berberine, a benzyl-tetra isoquinoline alkaloid found in Berberis sp.
Berberidaceae has long been a part of traditional Chinese and Ayurvedic medicine. Preclinical efficacy of berberine has been established in various cancers including colon Mao et al.
Despite large preclinical efficacy data, clinical trials related to the evaluation of true potential of berberine as an anticancer agent are limited. Most of the clinical trials have demonstrated the safety of berberine against other clinical conditions such as type 2 diabetes.
Curcumin, a yellow polyphenolic pigment, is an active ingredient in turmeric Curcuma longa; Zingiberaceae and is a highly promising chemopreventive agent. Several groups reported the chemopreventive and chemotherapeutic role of curcumin in different cancer cells including blood Taverna et al.
This has warranted studies in clinical trials to address pharmacokinetics, safety, and efficacy issues of curcumin in humans.
Despite bioavailability challenges, clinical trials with curcumin either alone or in combination as an anticancer agent have shown efficacy against several disease sites such as breast Bayet-Robert et al.
Latest information on various preclinical and clinical anticancer trials using curcumin is reviewed in Doello et al. administrated once weekly for 12 weeks against the advanced and metastatic breast cancer patients NCT Apart from this study, 18 other actively ongoing oncology-based trials using curcumin are registered on clinicaltrials.
Epigallocatechin EGCG is a major catechin found in green tea Camellia sinensis; Theaceae. Numerous studies using cell lines and animal models have established anticancer activity of EGCG Wang and Bachrach, ; Fujiki et al.
Moreover, recent study has suggested the use of EGCG in combination with indolecarbinol for better treatment outcomes in advanced ovarian cancer patients Kiselev et al.
Lycopene, a naturally occurring chemical that gives fruits and vegetables a red color, is abundantly found in red tomatoes Solanum lycopersicum; Solanaceae. In the meta-analysis of Chen et al. The study suggested avoiding the use of high doses of supplements in patients with prostatic intraepithelial neoplasia Gontero et al.
Interestingly, in a recent metabolomic study on men with increased PSA levels but no prostate cancer, intake of lycopene 15 mg along with GTCs EGCG mg for 6-months reduced the levels of circulating pyruvate.
The study using Mendelian randomization analysis suggested association of pyruvate level with prostate cancer risk Beynon et al. Overall, with the scarcity and heterogeneity of existing clinical evidences, the conclusions drawn can be conflicting or ambiguous.
In a phase I study on men with elevated PSA level in recurrent prostate cancer, pulverized muscadine grape skin extract MPX containing 4, mg resveratrol, compared with placebo, delayed the development of recurrence by lengthening the prostate specific antigen doubling time PSADT by 5.
Moreover, month treatment with MPX did not significantly prolong PSADT over two different doses, low mg or high 4, mg Paller et al. In a pilot study on patients with colorectal cancer with hepatic metastases, resveratrol 5. In another pilot study on 39 women at increased risk for breast cancer, trans-resveratrol 50 mg twice a day for 12 weeks decreased methylation of Ras association domain family 1 isoform A RASSF -1a, a gene associated with breast cancer, increased levels of trans-resveratrol and resveratrol-glucuronide in the circulation, and decreased cancer promoting PGE2 expression in the breast Zhu et al.
Recently, a clinical trial aimed at studying the effect of resveratrol 2. However No study results are posted so far on this clinical trial. Sulforaphane SFN is a dietary isothiocyanate found in cruciferous plants such as broccoli Brassica oleracea, Brassicaceae. Cipolla et al. conducted a double-blinded, randomized, placebo-controlled trial with SFN in 78 patients with increased PSA levels after radical prostatectomy.
Moreover, PSA slopes which were measured 2 months after SFN treatment remained the same Cipolla et al. In a single arm trial, Alumkal et al. Even though, the primary endpoint was not achieved, there was a significant increase in on-treatment PSADT as compared to pre-treatment PSADT 6.
The four major classes of clinically used plant-derived anticancer compounds include vinca alkaloids, taxane diterpenoids, camptothecin derivatives, and epipodophyllotoxin Figure 3 and Table 4.
Apart from these phytochemical classes, other plant-derived anticancer agents from different classes such as combretastatins, homoharringtonine omacetaxine mepesuccinate, cephalotaxine alkaloid , and ingenol mebutate are also used Figure 3 and Table 4.
Poor aqueous solubility and significant toxic side effects still remain the major concern and therefore, the current focus of research is toward eradicating the impact of these factors.
In this context, several analogues and prodrugs have been synthesized and methods have been devised to enhance aqueous solubility and tumor specificity. Brief description of a few phytochemicals which are used in cancer therapy is given below:.
Vinca alkaloids are a subset of drugs obtained from the pink periwinkle plant Catharanthus roseus Apocynaceae. The Vinca alkaloids achieve cytotoxic effects by binding to β-tubulin at a site distinct from that of the taxanes thereby inhibiting polymerization and assembly of microtubules, leading to metaphase arrest and cell death.
As the microtubules are associated with several other cellular functions such as maintenance of cell shape, motility, and transport between organelles, the vinca alkaloids affect both malignant and non-malignant cells in the non-mitotic cell cycle.
Vinblastine and vincristine are the two naturally isolated alkaloids that have been used in clinical oncology for almost 50 years. A series of semisynthetic analogues of these two alkaloids have been developed Table 4.
Vinorelbine and vindesine are the two effective semisynthetic analogues that are approved for clinical use. Recently, vinflunine, a second-generation gem-difluoromethylenated derivative of vinorelbine, has been approved for the treatment of second-line transitional cell carcinoma of the urothelium TCCU.
A comprehensive discussion of these agents is presented in the review by Martino et al. Taxanes represent promising anticancer drugs that were first isolated from the bark of the Yew tree.
Taxanes exert an anticancer affect by stabilization of microtubules, resulting in cell cycle arrest and aberrant mitosis. Paclitaxel, a natural product isolated from the bark and leaf of Taxus brevifolia and docetaxel, a semi synthetic derivative, is primarily used in breast, ovarian, pancreas, prostate, and lung cancer therapies.
A number of semisynthetic derivatives have been developed with improved cytotoxicity in resistant tumors, decreased toxicity, and improved solubility. For example, cabazitaxel a second-generation docetaxel derivative exhibits cytotoxic activity against various docetaxel-resistant tumors with less overall toxicity Kotsakis et al.
An additional characteristic of cabazitaxel is its ability to penetrate the blood—brain barrier in vivo , which is not achievable with other taxanes. Some of the paclitaxel analogues such as larotaxel, milataxel, ortataxel, and tesetaxel are currently undergoing clinical evaluation.
Camptothecin is a quinolone alkaloid isolated from the Chinese tree Camptotheca acuminata. Camptothecin complexes with type I DNA topoisomerase preventing both cleavage and religation of DNA leading to a DNA double-strand break and cytotoxicity Hertzberg et al.
At present, irinotecan and topotecan are the two FDA approved semi-synthetic camptothecin derivatives that are clinically active and less toxic than the parent compound. Irinotecan is prescribed for treatment of advanced cancers of the large intestine and rectum.
Whereas, topotecan is approved for the treatment of recurring ovarian, small cell lung cancer, and cervical cancer. Podophyllotoxin is a natural product isolated from Podophyllum peltatum and Podophyllum emodi Berberidaceae. Podophyllotoxin reversibly binds to tubulin, whereas its key derivatives etoposide and teniposide inhibit topoisomerase II, inducing topoisomerase II-mediated DNA cleavage.
Moreover, podophyllotoxin also exhibits potential anti-multidrug resistant MDR activity against diverse drug-resistant tumor cells. However, CIP failed in clinical trials due to lack of efficacy and unacceptable toxicity.
Ingenol mebutate IM is a hydrophobic ester of the diterpene ingenol isolated from common Australian plant Euphorbia peplus Euphorbiaceae. IM is approved for the topical treatment of actinic keratosis, a common skin condition that results from exposure to chronic ultraviolet radiation which can lead to squamous cell carcinoma, if not treated.
IM presents two mechanisms of action: at high concentrations ~— µM , it induces rapid induction of cell death in the treated area and at low concentrations ~0.
Pharmacology, mode of action, pharmacokinetics, dosing, and rout of administration of ingenol mebutate have been reviewed in more details by Skroza et al. Homoharringtonine HHT is a naturally-occurring ester of the alkaloid cephalotaxine isolated from various trees of the Cephalotaxus genus Cephalotaxaceae and is approved for the treatment of chronic myeloid leukemia.
HHT binds to the A-site cleft in the large ribosomal subunit, which affects chain elongation and prevents protein synthesis. The discovery and development of HHT and related compounds is comprehensively reviewed by Itokawa et al. Itokawa et al.
A semi-synthetic version of HHT, also known as omacetaxine mepesuccinate, has been reported to be an effective treatment for myelodysplastic syndromes MDS and chronic myelomonocytic leukemia CMML in patients with resistance and intolerance toward hypomethylating agents such as azacitidine and decitabine Short et al.
The combretastatins are a family of several cis-stilbenes from Cape bushwillow Combretum caffrum, Combretaceae , a shrub from South Africa. Compounds in the combretastatin class indirectly act on cancer cells by inhibiting tubulin polymerization causing disruption of the tumor endothelial cells lining the tumor vasculature, inducing rapid vascular collapse in solid tumors Tozer et al.
Combretastatin A1 and combretastatin A4 are the two naturally isolated compounds. Combretastatin A4 phosphate CA4P is a phosphate prodrug of combretastatin A4 which has been designated as an orphan drug by the US Food and Drug Administration FDA and is approved for the treatment of a range of thyroid and ovarian cancer.
Medicinal plants remain a crucial source in the search and development of new pharmacological leads. One major asset of medicinal plant-based drug discovery is the existence of ethnopharmacological information providing ideal opportunities to limit the huge diversity of possible leads to more promising ones.
A novel approach of integrated drug discovery where ethnopharmacological knowledge is supported by broad interdisciplinary forces involving medicinal chemistry, pharmacology, biochemistry, molecular, and cellular biology along with natural product chemistry is necessary to harvest the full potential of phytochemicals.
Additionally, the advances in analytical technology and computational methodologies, as well as the development of self-teaching artificial intelligence systems will facilitate the identification of new phytochemical lead entities for pharmacological evaluation.
In spite of the promise shown by phytochemicals as therapeutic agents in cancer, there are some limitations which need to be resolved. For instance, most of the phytochemicals studied at the preclinical stage lack insight into the molecular interaction with different signaling molecules.
To address issues related to molecular targets and pathways, in silico strategies like molecular docking need to be employed to understand the interaction of phytochemicals in different signaling pathways that can be further validated by various in vitro and in vivo models.
In most of the related clinical studies, the presence of methodological flaws including lack of control or placebo group, small sample sizes, and short duration of the trial are observed.
Therefore, for many phytochemicals, it is too early to conclude their anticancer actions and hence large-scale and well-controlled clinical trials are needed to validate their efficacies, adverse effects, and safeties before their use for the treatment of cancer.
Moreover, extensive standardization in terms of methods for evaluating their bioavailability, efficacy, safety, quality, composition, manufacturing processes, regulatory and approval practices, need to be carried out on the promising phytochemicals to meet the international standard.
Paradoxically, vast knowledge and experience in drug development are available in the pharmaceutical industry. Therefore, combining the benefits provided by both traditional and modern medicine has been previously suggested as a promising approach to reveal and to bring new plant-derived substances to market.
Synergistic or additional effects of combinations of chemotherapeutic agents and phytochemical compounds in cancer cells with acceptable side effects have been demonstrated Li et al. Thus, in recent years, the anticancer and chemopreventive properties of phytochemicals are attracting increasing interest from oncology researchers due to their low intrinsic toxicity in normal cells but prominent effects in cancerous cells Li et al.
In this review, an attempt has been made to provide a database of phytochemicals that are used for in vivo and clinical studies.
This information will be extremely useful to identify a series of additional plant-derived drugs to treat cancer with minimum side effects. OP and PR made substantial contributions to conception and design of the article. AC, PM, and MD contributed to the writing and editing of the manuscript.
AC and PM contributed to the designing of the figures and tables. All the authors read and approved the final manuscript for publication.
Author PR is on the Board of Directors in the company Innovation Biologicals Pvt Ltd, Pune, India. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Om Prakash is thankful to the Stanley S. Scott Cancer Center for providing financial support for the preparation and publication of this article. The authors are thankful to Adam Lassak and Suman Prakash for their help in revising, editing, and formatting the citation list. Abrams, S.
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Metrics dtudies. Cancer is currently the second leading Glucagon hormone effects Anti-cancer research studies death globally and is expected to be responsible for approximately 9. Immune supportive caffeine extract an unprecedented gesearch of the rrsearch pathways that drive Reesearch development and progression of human cancers, Anit-cancer targeted therapies Anti-cajcer become an exciting new development for anti-cancer medicine. These targeted therapies, also known as biologic therapies, have become a major modality of medical treatment, by acting to block the growth of cancer cells by specifically targeting molecules required for cell growth and tumorigenesis. Due to their specificity, these new therapies are expected to have better efficacy and limited adverse side effects when compared with other treatment options, including hormonal and cytotoxic therapies. In this review, we explore the clinical development, successes and challenges facing targeted anti-cancer therapies, including both small molecule inhibitors and antibody targeted therapies. Corrigendum: Tart cherry juice for cholesterol in Cancer Treatment: Stuies Preclinical Studies to Clinical Studirs. Anti-cancer research studies is Anti-cqncer Anti-cancer research studies health problem that continues to be a leading cause of death worldwide. Increasing knowledge of the molecular mechanisms underlying Studiee progression has led to the development of a vast number of anticancer drugs. However, the use of chemically synthesized drugs has not significantly improved the overall survival rate over the past few decades. As a result, new strategies and novel chemoprevention agents are needed to complement current cancer therapies to improve efficiency. Naturally occurring compounds from plants known as phytochemicals, serve as vital resources for novel drugs and are also sources for cancer therapy.
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